Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-δ Pathway

Peroxisome proliferator-activated receptor delta (PPAR-delta) is a nuclear receptor transcription factor that regulates gene expression during development and disease states, such as cancer. However, the precise role of PPAR-delta during tumorigenesis is not well understood. Recent data suggest that PPAR-delta may have context-specific oncogenic and tumor-suppressive roles depending on the tissue, cell-type, or diet-induced physiology in question. For example, in the intestine, pro-obesity diets, such as a high-fat diet (HFD), are associated with increased colorectal cancer incidence. Interestingly, many of the effects of an HFD in the stem and progenitor cell compartment are driven by a robust PPAR-delta program and contribute to the early steps of intestinal tumorigenesis. Importantly, the PPAR-delta pathway or its downstream mediators may serve as therapeutic intervention points or biomarkers in colon cancer that arise in patients who are obese. Although potent PPAR-delta agonists and antagonists exist, their clinical utility may be enhanced by uncovering how PPAR-delta mediates tumorigenesis in diverse tissues and cell types as well as in response to diet. (C) 2016 AACR.